ABSTRACT Massive burns are associated with a persistent and sustained hypermetabolic response characterized by elevated levels of circulating catecholamines, cytokines and cortisol, which cause muscle wasting, immunodeficiency, organ dysfunction and a delay in wound healing. Insulin and propranolol have demonstrated an activity in selected patients which ameliorates the responses to burn with minimal associated side effects. We hypothesize that during acute hospitalization, propranolol titrated to reduce heart rate by 20%, and/or treatment with insulin titrated to a dose to maintain blood glucose between 80-110 mg/dL will reduce cardiovascula work, infections and improve wound healing, muscle wasting, inflammation, and recovery in both children and adults with severe thermal injuries. The specific aims are: 1): Determine the mechanisms whereby insulin, propranolol or their combination (insulin plus propranolol) affect whole body and organ function on a clinical level. 1a) We will determine organ function and clinical outcome by measuring cardiovascular responses, hypermetabolism, hormonal profile, body composition, incidence of infection and sepsis and their alterations with insulin, propranolol, or their combination. 1b) Another major aim of the present study is to determine the effect of insulin, propranolol and their combination on mortality. 2) Determine the mechanisms whereby insulin, propranolol and their combination exert their effects in muscle, wound, and liver on a cellular level. The acute effects of these drugs on cardiac work, protein and fat kinetics, glucose levels, wound healing, and body composition will be analyzed using a randomized prospective design in which compared. In this application we propose that insulin in combination with propranolol will benefit burned patients more than either alone, by improving muscle protein build-up, maintaining organ function, promoting rapid wound healing, decreasing cardiac work, improving mitochondrial function, and decreasing infections.